A longitudinal study of cytochrome P450 2D6 (CYP2D6) activity during adolescence.

CYP2D6 substrates are among the most highly prescribed medications in teenagers and also commonly associated with serious adverse events. To investigate the relative contributions of genetic variation, growth, and development on CYP2D6 activity during puberty, healthy children and adolescents 7-15 years of age at enrollment participated in a longitudinal phenotyping study involving administration of 0.3 mg/kg dextromethorphan (DM) and 4-h urine collection every 6 months for 3 years (7 total visits). At each visit, height, weight, and sexual maturity were recorded, and CYP2D6 activity was determined as the urinary molar ratio of DM to its metabolite dextrorphan (DX). A total of 188 participants completed at least one visit, and 102 completed all seven study visits. Following univariate analysis, only CYP2D6 activity score (p < 0.001), urinary pH (p < 0.001), weight (p = 0.018), and attention-deficit/hyperactivity disorder (ADHD) diagnosis (p < 0.001) were significantly correlated with log(DM/DX). Results of linear mixed model analysis with random intercept, random slope covariance structure revealed that CYP2D6 activity score had the strongest effect on log(DM/DX), with model-estimated average log(DM/DX) being 3.8 SDs higher for poor metabolizers than for patients with activity score 3. A moderate effect on log(DM/DX) was observed for sex, and smaller effects were observed for ADHD diagnosis and urinary pH. The log(DM/DX) did not change meaningfully with age or pubertal development. CYP2D6 genotype remains the single, largest determinant of variability in CYP2D6 activity during puberty. Incorporation of genotype-based dosing guidelines should be considered for CYP2D6 substrates given the prevalent use of these agents in this pediatric age group.

Griseofulvin Only Modestly Diminishes Persistence of Trichophyton tonsurans on the Scalp of Carriers.

OBJECTIVES: Using genetic strain typing, we previously identified a high rate of T. tonsurans carriage among preschool-aged children attending an urban daycare center. No treatment was provided as part of the observational study; however, children when symptomatic were treated in accordance with daycare policies. This retrospective investigation examines antifungal drug therapy received during the previous investigation and characterizes the impact of treatment on persistence of the fungus on the scalp. METHODS: Children in whom serial typeable isolates of T. tonsurans were recovered were eligible for evaluation. Clinic charts were reviewed and dispensing records obtained from the primary pharmacies serving the daycare. Infection patterns were examined before and after treatment. RESULTS: We identified 72 dispensing records for 53 children, all of whom received griseofulvin. Nine children could not be evaluated because treatment was coincident with their last study visit. Thus, 63 treatment events in 44 children with 331 discrete infection events remained. After a single course of griseofulvin, 22.7% of children became culture negative, 6.8% acquired another strain of T. tonsurans and, 70.5% remained persistently positive with the same strain carried prior to treatment. Among those receiving a second course of therapy, 54% remained positive and the cumulative percent of children that became culture negative increased to 36.4%. If children subsequently acquiring a different strain are considered together with those that became culture negative, cumulative strain clearance was observed in 43% of children. Neither the griseofulvin dose nor the duration of time over which children were infected prior to treatment differed between those that remained positive and those that became negative. CONCLUSIONS: Griseofulvin eradicates dermatophyte scalp carriage in less than one-half of preschool-aged children receiving between one and four 4-week courses of the drug.

Tracking Trichophyton tonsurans through a large urban child care center: defining infection prevalence and transmission patterns by molecular strain typing.

OBJECTIVES: Trichophyton tonsurans is the single most common cause of pediatric dermatophytoses in North America and is observed with increasing frequency in other countries. This investigation was designed to gain insight into the natural course of T. tonsurans infection. PATIENTS AND METHODS: This 2-year prospective, longitudinal study evaluated all preschool-aged children attending a single child care center. Scalp cultures were collected monthly from each child in attendance, and the presence of disease symptoms recorded at each visit. Dermatophyte genotype was assigned based on the combination of stable sequence variations (2 length variants, 8 single-nucleotide polymorphisms, a 10-base pair insertion, a 14-base pair deletion) present in 2 gene loci. RESULTS: A total of 3541 scalp cultures were collected from 446 children during 24 months. Twenty-two percent to 51% of scalp cultures per month were positive, contributing 1390 fungal cultures of which 1048 were typeable. Among children with multiple typeable isolates, 51% exclusively carried the same strain, 37% demonstrated a single predominant strain with secondary strains transiently acquired, and 12% harbored a different strain of T. tonsurans with each typeable culture. The probability that the same strain persisted in subsequent months was 0.898 and unlikely to have arisen by chance. Rates of symptomatic disease were significantly different between exclusive, predominant, and transient carriers of T. tonsurans. CONCLUSIONS: In contrast to dermatophyte infections in older individuals, where symptomatic disease seems to be a consequence of pathogen acquisition and carriers can be traced to an index case, in this preschool-aged population infection was endemic, and symptomatic disease seemed to represent activation of a single strain that persisted on the scalp.